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Results for “computational design”

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At least 73 records · Page 4Linked to original sources
PubMed2003

Computational design and characterization of a monomeric helical dinuclear metalloprotein.

The de novo design of di-iron proteins is an important step towards understanding the diversity of function among this complex family of metalloenzymes. Previous designs of due ferro (DF) proteins have resulted in tetrameric and dimeric four-helix bundles having crystallographically well-defined structures and active-site geometries. Here, the design and characterization of DFsc, a 114 residue monomeric four-helix bundle, is presented. The backbone was modeled using previous oligomeric structures and appropriate inter-helical turns. The identities of 26 residues were predetermined, including the primary and secondary ligands in the active site, residues involved in active site accessibility, and the gamma beta gamma beta turn between helices 2 and 3. The remaining 88 amino acid residues were determined using statistical computer aided design, which is based upon a recent statistical theory of protein sequences. Rather than sampling sequences, the theory directly provides the site-specific amino acid probabilities, which are then used to guide sequence design. The resulting sequence (DFsc) expresses well in Escherichia coli and is highly soluble. Sedimentation studies confirm that the protein is monomeric in solution. Circular dichroism spectra are consistent with the helical content of the target structure. The protein is structured in both the apo and the holo forms, with the metal-bound form exhibiting increased stability. DFsc stoichiometrically binds a variety of divalent metal ions, including Zn(II), Co(II), Fe(II), and Mn(II), with micromolar affinities. 15N HSQC NMR spectra of both the apo and Zn(II) proteins reveal excellent dispersion with evidence of a significant structural change upon metal binding. DFsc is then a realization of complete de novo design, where backbone structure, activity, and sequence are specified in the design process.

Amino Acid Sequence↗
PubMed1999

The management of endodontically treated teeth using a Computer-Aided Design and Computer-Assisted Manufacturing/Computer-Aided Design and Computer-Integrated Manufacturing system.

This article introduces a new approach for restoring endodontically treated posterior teeth. Significantly reduced natural tooth structure often remains not only because of previous restorative measures but also because of endodontic procedures. Cast restorations for these teeth are almost universally recommended. The exception to this is the rare instance in which only conservative endodontic access openings exist in teeth presenting with no former existing restorations. Typically, multiple clinical appointments are required to complete the final cast restoration. This article presents Computer-Aided Design and Computer-Assisted Manufacturing/Computer-Aided Design and Computer-Integrated Manufacturing applications for restorative dentistry that provide the necessary care in an expeditious manner.

Ceramics↗
PubMed2003

Computational design of a water-soluble analog of phospholamban.

Membrane proteins and water-soluble proteins share a similar core. This similarity suggests that it should be possible to water-solubilize membrane proteins by mutating only their lipid-exposed residues. We have developed computational tools to design water-soluble variants of helical membrane proteins, using the pentameric phospholamban (PLB) as our test case. To water-solublize PLB, the membrane-exposed positions were changed to polar or charged amino acids, while the putative core was left unaltered. We generated water-soluble phospholamban (WSPLB), and compared its properties to its predecessor PLB. In aqueous solution, WSPLB mimics all of the reported properties of PLB including oligomerization state, helical structure, and stabilization upon phosphorylation. We also characterized the truncated mutant WSPLB (21-52) comprising only the former transmembrane segment of PLB. This peptide shows a decreased specificity for forming a pentameric oligomerization state.

Algorithms↗
PubMed2003

Computational design strategies for combinatorial libraries.

Medicinal chemistry principles are being increasingly applied to the design of smaller, high purity, information-rich libraries. Recent computational advances in statistical methodology, the design of libraries to reduce ADMET problems, targeting protein families and revisiting natural products as sources of inspiration for scaffolds and reagents are all areas of progressive research.

Animals↗
PubMed1991

Computer design and fabrication of custom-contoured seating.

This article describes the development of a computer-controlled system for measuring anatomical contours and forces at the interface with seat surfaces. The system was designed to eliminate the cause of pressure sores, which are a major problem for wheelchair-bound individuals. A parallel and compatible system also has been developed for the rapid, precise, and cost-effective fabrication of custom-contoured seat cushions and other body supports from a range of open- and closed-cell foam materials.

Algorithms↗
PubMed2005

Long oligonucleotide microarrays in wheat: evaluation of hybridization signal amplification and an oligonucleotide-design computer script.

A computer script was written in the Perl language to design equal-length long oligonucleotides from DNA sequences. The script allows the user to specify G + C content, melting temperature, self-complementarity, the maximum number of contiguous duplicate bases, whether to start with the first start codon and whether to report reverse complements. Microarrays were fabricated with 95 oligonucleotides (60 mers) representing 41 genes. The microarray was interrogated with cDNA from roots and shoots of two near-isogenic lines and a commercial cultivar of Triticum aestivum L. (hexaploid wheat) challenged with cold temperature, hot temperature, or the biological control bacterium Pseudomonas fluorescens. Self-complementarity of the oligonucleotides was negatively correlated with signal intensity in 23 of 54 arrays (39%; P <0.01). Tyramide signal amplification was essential for signal generation and detection. Genes involved in signal transduction pathways responded similarly following exposure to cold, heat and P. fluorescens, suggesting intersection of the pathways involved in response to these disparate stress factors. Microarray results were corroborated by quantitative real-time PCR in 75% of samples assayed. We conclude that long oligonucleotide microarrays for interrogation with cDNA from hexaploid wheat should be constructed from oligonucleotides having minimal self complementarity that also meet user-specified requirements of length, G + C content and melting temperature; multiple oligonucleotides should be used to represent each gene; and Tyramide signal amplification is useful in wheat oligonucleotide microarray studies.

Base Sequence↗
PubMed1990

A computer designed graph for administration of atracurium by i.v. infusion.

A bi-exponential mathematical computer model was used to develop a guidance graph for atracurium infusions. The model permitted variation in infusion rates, in pharmacokinetic parameters and in "effect" thresholds. Systematic experiments revealed a relationship between the rate of recovery from a fixed bolus loading dose and the most appropriate initial infusion rate. This relationship was expressed as a guidance graph or "ready reckoner". The quality of guidance was assessed in 50 anaesthetics, given consecutively. In 39 patients optimal myoneural block for surgery was maintained for the duration of the infusion without adjustments or supplementary bolus doses. The mean operating time was 92 min and the mean duration of infusion was 59 min.

Adult↗
PubMed1993

Computer design of bioactive compounds based on 3-D properties of ligands.

3-D database searching has many uses for a medicinal chemist. It can aid in the design of compounds to probe or to mimic the bioactive conformation of a natural ligand or to fit a hypothetical or experimental structure of a binding site. It also can identify existing molecules that meet these criteria--new uses for old molecules. If one has a database of active compounds, 3-D searching can validate or refute a pharmacophore hypothesis. The CoMFA method of 3DQSAR can be used to forecast the potency of the designed analogs. Also, the integration of CoMFA and 3-D searching concepts provides a framework for the design of a good series for CoMFA. In addition, CoMFA 3DQSAR coefficients provide a model of the binding site to facilitate the design of compounds that fit the pharmacophore and do not hit sterically unfavorable regions.

Animals↗
PubMed1996

Computer design and syntheses of antiulcer compounds. 2nd Communication: N-substituted N'-[3-[3-(1-piperidinomethyl)phenoxy]propyl]ureas.

The in vitro and in vivo antiulcer effect of a series of N-substituted N'3-[3-(1-piperidinomethyl)phenoxy]propyl]ureas was modeled by making use of the OASIS computer system for QSAR analysis. Various research schemes were employed depending on structural representation of chemicals under investigation, such as non-protonated (neutral), protonated at the piperidine and urea fragmental nitrogens, and with intramolecular hydrogen binding. According to the modeling results, it is likely a variety of structural forms of antagonist molecules to take part in the receptor interaction. The QSAR study showed that the larger the electron acceptor properties of the nitrogen and oxygen atoms of the urea fragment, the higher is in vitro and in vivo activity of the antagonists.

Anti-Ulcer Agents↗
PubMed2000

Chemical development of latent fingerprints: computational design of ninhydrin analogues.

The design of chemical compounds for development of latent fingerprints is explored computationally. Our main findings are: (a) We show why past attempts to improve the widely used ninhydrin gave relatively small improvements (referring to color only). The optical transition is connected with a "transition core" and therefore is influenced little by substitution on the aromatic rings. (b) We propose new analogues of ninhydrin with a significant potential such as thiono derivatives.

Adsorption↗
PubMed2006

Computational design of heterochiral peptides against a helical target.

Polypeptides incorporating D-amino acids occasionally occur in nature and are an important class of pharmaceutical molecules. With the use of heterochiral Monte Carlo (HCMC), a method inspired by the de novo design of proteins, we develop peptide scaffolds for interacting with a molecular target, a left-handed alpha-helix. The HCMC approach concurrently seeks to optimize a peptide sequence, its internal conformation, and its docked conformation with a target surface. Several major classes of interactions are observed: (1) homochiral interactions between two alphaL helices, (2) heterochiral interactions between an alphaL and an alphaR helix, and (3) heterochiral interactions between the alphaL target and novel nonhelical structures. We explore the application of HCMC to simulating the preferential enantioselectivity of heterochiral complexes. Implications for biomimetic design in molecular recognition are discussed.

Alanine↗
PubMedDate not supplied

Absorbed dose resulting from a specially designed computed tomography technique for examination of the urinary bladder.

The absorbed spatial dose distribution resulting from a specially designed CT protocol for examination of the urinary bladder has been investigated with TLD rods in a body phantom containing tissue equivalent material. The CT examination consisted of scout view and both pre- and postcontrast scan series with 5 mm slice thickness and 5 mm unscanned intervals between successive scans. Cross-sectional dose distribution for one scan in the plane of the ovaries was measured as well as the dose profile for one scan along a line through the ovary parallel to the axis of rotation. Based on these measurements, the dose resulting from the whole CT examination was calculated, both with contiguous and noncontiguous scans. The ovarian dose was calculated for different positions of the ovaries in relation to the scanned area. The absorbed dose varied between 8.3 mGy and 9.7 mGy with the actual technique used. When contiguous scans with the same thickness were taken, the ovarian dose increased with a factor from 1.7 to 1.9. The dose resulting from the CT protocol of the urinary bladder was of the same magnitude as absorbed dose resulting from urography. When the diagnostic gain from a precise definition of tumor extent was taken into account, the dose resulting from the CT protocol was judged acceptable.

Female↗